病灶区灌注噻唑烷二酮对家兔脑出血模型血肿周围脑组织过氧化酶活化增生受体γ及血脑屏障通透性的影响

Intracerebral hemorrhage(ICH) often triggers a series of adverse events causing secondary brain insults and leads to severe neurological deficits. The increasing evidences indicate that oxidative stress plays a prominent role in the ICH-induced secondary brain damages.Activation of the peroxisome proliferator-activated receptor γ(PPARγ) might be reduce the the oxidative stress by inducing the expression of antioxidant catalase and copper/zinc superoxide dismutase (SOD).In our previous studies, we successfully established a model of intracerebral hematoma in rabbit, and optimized the time window for removing hematoma by minimally invasive procedure for evacuation, as well as studied the associated pathological injury.We hypothesize that activation of PPARγ combined with performing the minimally invaisive procedures for ICH evacation may significantly alleviate the pathological injury after intracerebral hematoma.The purposes of this study are to observe the preventive and therapeutic effects of PPARγ agonists Thiazolidinediones combined with the minimally invasive procedures for evacuation of intracerebral hematoma on the perihematomal secondary brain damages.Heathy rabbits are selected to establish the model of intracerebral hemorrhage by stereotactically infusing arterial blood into the animal`s basal ganglions.The rabbits are assigned to different groups for observation.The stereotactically minimally invasive surgery are used to evacuate the ICH followed by injection of Thiazolidinediones into the hematoma cavity.The perihematomal brain tissues are collected to determine the PPARγ,the CD36,the antioxidant catalase and SOD,the glutamate content,the blood-brain-barrier(BBB) permeability,as well as the brain water content(BWC).The neurofunction of the animal are also evaluated.The indexes mentioned above in the treatment group are compared with other groups.Performing the minimally invasive procedurs to evacuate the ICH followed by Thiazolidinediones might increase the level of PPARγ,the CD36,the expression of antioxidant catalase and SOD,simultaneously the perihematomal glutamate level,the BBB permeability as well as the BWC are decreased so that the secondary brain damages are reduced. Treatments with the agonists of PPARγ during/ after minimally invasive procedures may serve as a therapeutic strategy for intracerebral hematoma.

血肿周围继发性脑损伤是颅内出血的严重并发症，越来越多的实验证据表明氧化应激在颅内血肿所致的继发性脑组织损伤中发挥重要作用，而激活过氧化酶活化增生受体γ(PPARγ)可通过增加抗氧化剂和铜锌超氧化物歧化酶(SOD)的表达来降低氧化应激；我们前期的研究证明及时进行微创清除术能有效降低继发性脑组织损伤，因此，本研究拟观察PPARγ激动剂噻唑烷二酮结合微创颅内血肿清除术对病灶周围继发性脑损伤的治疗作用；选择健康家兔建立脑出血模型并分为不同观察组，采用立体定向微创技术清除颅内血肿，继而于血肿区内灌注噻唑烷二酮类药物进行干预，以病灶周围PPARγ表达、抗氧化剂过氧化氢酶、CD36、SOD、血脑屏障通透性、谷氨酸水平等为指标，观察病灶周围继发性脑损伤的变化；预期结果为微创颅内血肿清除术后给予噻唑烷二酮可明显减轻病灶周围继发性脑损伤程度，该项目的完成有望对病灶周围继发性脑损伤的治疗提供有效手段。

本课题以脑出血细胞模型、家兔模型以及脑出血患者为对象，采用立体定向技术清除颅内血肿然后病灶区灌注噻唑烷二酮激活PPARγ受体，以小胶质细胞的吞噬能力、抗氧化应激指标以及家兔病灶周围BBB通透性、脑含水量、神经毒性物质含量等为观察指标，判断立体定向微创技术清除颅内血肿结合病灶区灌注PPARγ激动剂对继发性脑损伤的作用;在患者则主要采用弥散张量成像成像技术观察内囊神经纤维束的变化及神经功能恢复情况。有以下主要发现：.1.首次发现PPARγ抗氧化作用可能是通过Nrf2调控下游基因实现的，罗格列酮可通过激活PPARγ来增加其下游抗氧化基因的表达，发挥抗氧化作用，罗格列酮可通过细胞凋亡途径增加小胶质表面CD36的表达增强凝血酶诱导的小胶质细胞吞噬作用，既往研究未见报道；.2.首次应用微创血肿清除术结合激活小胶质细胞的药物来治疗颅内血肿引发的继发性脑损伤，我们的这一研究将为治疗颅内血肿的继发性脑损伤提供新的治疗方案和实验基础，这在国内外罕见；.3. 本课题首次发现采用立体定向微创技术治疗脑出血联合病灶区灌注罗格列酮可明显促进PPARγ表达，减少病灶区谷氨酸含量、脑含水量，减低神经功能评分、血脑屏障通透性，抑制咬合蛋白、闭合小环蛋白１及ET-1的表达，可能比单独的实施立体定向颅内血肿清除术治疗更有效地降低继发性脑损伤。.4.本课题组用家兔颅内血肿模型，采用立体定向微创清除术为手段清除血肿，继而在病灶区灌注噻唑烷二酮激活PPARγ受体来提高脑内吞噬细胞的功能，同时减弱氧化应激来治疗继发性脑损伤，在既往脑出血的实验研究中未见到相关报道；本研究有望揭示治疗颅内血肿继发性脑损伤的新方案和潜在药物。

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